Reverse overshot water-wheel retroendocytosis of Apo Transferrin extrudes cellular iron

Sheokand, Navdeep; Malhotra, Himanshu; Chauhan, Anoop Singh; Kumar, Manoj; Chaudhary, Surbhi; Patidar, Anil; Boradia, Vishant Mahendra; Raje, Chaaya Iyengar; Raje, Manoj

doi:10.1242/jcs.180356

Cited by 8 publications

(7 citation statements)

References 39 publications

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“…FPN (SLC40A1), a member of the large solute carrier gene family (slc) is a transmembrane protein primarily expressed in macrophages, duodenal, and hepatic cells and is considered the only (or major) iron exporter, a role confirmed by the finding that mice with global FPN inactivation died during embryonic development . However, a recent study suggested an alternative pathway of cellular iron export mediated by GAPDH‐dependent retroendocytosis of iron‐loaded Tf . In addition, considering that NO has a high affinity for iron and can form dinitrosyl‐dithiol iron complexes (DNIC) and that iron can also be bound to GSH, the multidrug resistance protein ATP‐binding cassette subfamily C 1 (ABCC1), which exports both DNIC and GSH out of cells, may represent a way of iron efflux, particularly in activated murine macrophages that synthesize large amounts of NO .…”

Section: Iron Exportmentioning

confidence: 99%

Molecular regulation of cellular iron balance

et al. 2017

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Handling a life-supporting yet redox-active metal like iron represents a significant challenge to cells and organisms that must not only tightly balance intra- and extracellular iron concentrations but also chaperone it during its journey from its point of entry to final destinations, to prevent inappropriate generation of damaging reactive oxygen species. Accordingly, regulatory mechanisms have been developed to maintain appropriate cellular and body iron levels. In intracellular compartments, about 95% of iron is protein-bound and the expression of the major proteins of iron metabolism is controlled by an integrated and dynamic system involving multilayered levels of regulation. However, dysregulation of iron homeostasis, which could result from both iron-related and unrelated effectors, may occur and have important pathological consequences in a number of human disorders. In this review, we describe the current understanding of the mechanisms that keep cellular iron balance and outline recent advances that increased our knowledge of the molecular physiology of iron metabolism. © 2017 IUBMB Life, 69(6):389-398, 2017.

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Section: Iron Exportmentioning

confidence: 99%

Molecular regulation of cellular iron balance

et al. 2017

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“…In addition to TfR1 and TfR2, the multifunctional molecule GAPDH has been reported to work as a TfR in different cell types (Raje et al, 2007; Kumar et al, 2012) with a role in iron uptake and/or iron export (Sheokand et al, 2016) and as a chaperone for intracellular heme traffic (Sweeny et al, 2018). Relevant to brain and excitotoxicity, GAPDH interacts with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype of glutamate receptors in the neurons without glutamate stimulation and has also been reported to be pivotal for axon development (Lee et al, 2016).…”

Section: Iron Uptake and Handling By Parenchymal Brain Cellsmentioning

confidence: 99%

Deciphering the Iron Side of Stroke: Neurodegeneration at the Crossroads Between Iron Dyshomeostasis, Excitotoxicity, and Ferroptosis

DeGregorio-Rocasolano

2019

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In general, iron represents a double-edged sword in metabolism in most tissues, especially in the brain. Although the high metabolic demands of brain cells require iron as a redox-active metal for ATP-producing enzymes, the brain is highly vulnerable to the devastating consequences of excessive iron-induced oxidative stress and, as recently found, to ferroptosis as well. The blood–brain barrier (BBB) protects the brain from fluctuations in systemic iron. Under pathological conditions, especially in acute brain pathologies such as stroke, the BBB is disrupted, and iron pools from the blood gain sudden access to the brain parenchyma, which is crucial in mediating stroke-induced neurodegeneration. Each brain cell type reacts with changes in their expression of proteins involved in iron uptake, efflux, storage, and mobilization to preserve its internal iron homeostasis, with specific organelles such as mitochondria showing specialized responses. However, during ischemia, neurons are challenged with excess extracellular glutamate in the presence of high levels of extracellular iron; this causes glutamate receptor overactivation that boosts neuronal iron uptake and a subsequent overproduction of membrane peroxides. This glutamate-driven neuronal death can be attenuated by iron-chelating compounds or free radical scavenger molecules. Moreover, vascular wall rupture in hemorrhagic stroke results in the accumulation and lysis of iron-rich red blood cells at the brain parenchyma and the subsequent presence of hemoglobin and heme iron at the extracellular milieu, thereby contributing to iron-induced lipid peroxidation and cell death. This review summarizes recent progresses made in understanding the ferroptosis component underlying both ischemic and hemorrhagic stroke subtypes.

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“…While according to current dogma, iron leaves the cell principally via Fpn transport, it is worth noting that some data suggest that cellular ferritin efflux may be a mechanism for Fe 3+ export (42)(43)(44)(45). Moreover, a recent study proposed an alternative iron export pathway, via GAPDH-mediated retro-endocytosis of iron-loaded Tf (46), and an important but underappreciated iron-release mechanism employed by tumor-associated Mɸs (TAMs) to kill cancer cells has been described. In this context, M1-like TAMs produce NO via iNOS that evokes iron efflux from cancer cells (47)(48)(49).…”

Section: Introductionmentioning

confidence: 99%